Stemming the opioid-induced pain cascade via cannabinoid modulation

通过大麻素调节阻止阿片类药物引起的疼痛级联反应

基本信息

批准号：
10218325
负责人：
Steven G. Kinsey
金额：
$ 20.13万
依托单位：
UNIVERSITY OF CONNECTICUT STORRS
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10218325
关键词：
2-arachidonylglycerol Acute Analgesics Animal Model Animals Anti-Inflammatory Agents Antiinflammatory Effect Attention Attenuated Behavior Behavioral Behavioral Model Binding Biological CNR1 gene CNR2 gene Cannabinoids Cannabis Chemicals Chronic Data Depressed mood Development Disease Drug Targeting Drug abuse Endocannabinoids Enzymes Experimental Animal Model Female Genetic Glycerol Goals Gold Harvest Human Hyperalgesia Immunologics In Vitro Incubated Individual Inflammation Inflammatory Injury Literature MAGL inhibitor Measures Modeling Monoacylglycerol Lipases Morphine Morphine Users Motivation Mus Needlestick Injuries Neurons Opiate Addiction Opioid Pain Painless Pathway interactions Perception Peripheral Pharmaceutical Preparations Pharmacology Physiological Physiological Processes Postoperative Pain Postoperative Period Property Quality of life Relapse Reporting Research Risk Spinal Cord Splenocyte Stimulus Substance Use Disorder Surface Surgical incisions Surgical sutures TLR4 gene Testing Therapeutic Therapeutic Intervention Thermal Hyperalgesias Tissues Translational Research Treatment outcome Withdrawal Woman allodynia base cannabinoid receptor cannabinoid receptor antagonist combat conditioning cytokine dependence relapse desensitization drug relapse effective therapy endogenous cannabinoid system exogenous cannabinoid inflammatory pain macrophage male marijuana use mechanical allodynia monocyte morphine administration mu opioid receptors neurobehavioral novel strategies opioid abuse opioid epidemic opioid exposure opioid sparing opioid use opioid use disorder opioid user opioid withdrawal pain perception pain sensitivity painful neuropathy preclinical study prescription opioid prevent receptor relating to nervous system response sex side effect stem substance abuse treatment

项目摘要

Despite their abuse potential, opioids remain a gold standard analgesic. One of the lesser discussed effects of chronic opioid use is opioid induced hyperalgesia (OIH), or increased pain sensitivity in some users. OIH persists for a longer duration than opioid withdrawal and may contribute to drug seeking and relapse in people with substance use disorders. The physiological causes of OIH are caused by (1) repeated µ opioid activation and desensitization, and (2) activation of inflammatory pathways by morphine binding to Toll-like receptor 4. Cannabinoids have well established analgesic and anti-inflammatory properties. Endogenous cannabinoids (i.e., endocannabinoids) have anti-inflammatory effects with limited intoxicating effects, as compared with exogenous cannabinoids. The proposed study will use an experimental animal model of repeated morphine exposure, followed by paw incision injury. Our goal is to test the hypothesis that inhibition of the endocannabinoid catabolic enzyme monoacylglycerol lipase (MAGL) decreases pain and inflammation caused by repeated morphine treatment. Male and female mice will be repeatedly administered morphine or vehicle, in the presence of increased endocannabinoid tone, for four days. Endocannabinoid tone will be increased by either chemical inhibition of MAGL, or genetic deletion of MAGL globally or on neurons only. Then, a small incision will be made and sutured closed in the plantar surface of one hindpaw, to model postoperative hyperalgesia. Mice will be tested repeatedly for pain- induced, pain-suppressed, and pain conditioning behavioral models. Endocannabinoid receptor mechanism will be determined using selective CB1 and CB2 cannabinoid receptor antagonists. Paw tissue will be collected to quantify proinflammatory cytokine levels, and individual cytokine levels will be correlated with pain-related behaviors. The anti-inflammatory mechanisms of endocannabinoid modulation will be further probed in vitro, using isolated macrophages/monocytes. Extant studies of preclinical OIH models have used male animals almost exclusively. Because women may be at increased risk for developing OIH, we will include sufficient numbers of both female and male mice to investigate Sex as a Biological Variable. In addition to increasing basic understanding of the underlying neural and immunological mechanisms that contribute to opioid-induced hyperalgesia, our translational research goal is to develop treatments for substance abuse disorders.

尽管具有滥用潜力，但阿片类药物仍然是黄金标准镇痛药。较小的讨论的慢性OOid使用的影响是Ooid诱导的痛觉过敏（OIH）或疼痛增加某些用户的敏感性。 OIH持续时间比阿片类药物撤离更长的时间在患有药物使用障碍的患者中寻求和继电器。这 OIH的生理原因是由（1）重复的µ阿片类药物激活和脱敏引起的，（2）吗啡结合与Toll样受体4的激活炎症途径。大麻素具有良好的镇痛和抗炎特性。内源性大麻素（即内源性大麻素）具有抗炎作用，陶醉有限与外源性大麻素相比，影响。拟议的研究将使用重复吗啡暴露的实验动物模型，然后进行爪切口损伤。我们的目标是检验抑制内源性大麻素分解代谢酶的假设单酰基甘油脂肪酶（MAGL）减轻了由重复引起的疼痛和炎症吗啡治疗。雄性和雌性小鼠将反复使用吗啡或车辆，在存在内源性大麻素张力的情况下，持续了四天。内源性大麻素的张力将是通过MAGL的化学抑制或全球MAGL的遗传缺失而增加仅神经元。然后，将在足底表面进行小切口并缝合一个后爪，以模拟术后痛觉过敏。小鼠将反复测试疼痛 - 诱导，抑制疼痛和疼痛调节行为模型。内源性大麻素接收器机制将使用选择性CB1和CB2大麻素受体拮抗剂确定。将收集爪组织以量化促炎性细胞因子水平和单个细胞因子水平将与疼痛相关的行为相关。抗炎机制内源性大麻素调节将在体外进一步探测，并使用孤立巨噬细胞/单核细胞。临床前OIH模型的现有研究使用了雄性动物几乎完全。因为妇女可能会增加发展OIH的风险，我们将包括足够数量的雌性和雄性小鼠，以调查性别作为生物学多变的。除了对基本神经和有助于阿片类药物引起的痛觉过敏的免疫机制，我们的翻译研究目标是开发滥用药物疾病的治疗方法。